Zinc transporter 8 (ZNT8), predominantly located in pancreatic β-cells, is essential for insulincrystallization and secretion. Its genetic variations are associated with heightened Type 2 Diabetes (T2D) risks. Somatostatin (SST), widely expressed in the brain and other tissues, including pancreatic islets, primarily functions as an inhibitory hormone. Within the pancreas, SST modulates glucose metabolism by affecting insulin and glucagon secretions. This study unravels the intricate roles of ZNT8 and SST in maintaining glucose and lipid metabolism. Our research explores the impacts of maternal Sst deficiency on the metabolic health trajectory of the progeny. Results indicate that descendants from mothers with Sst deficiencies experience hindered pancreatic islet development, rendering them more susceptible to diet-induced obesity and T2D. Further, we probed the concurrent effects of Znt8 and Sst deficits in mice on a high-fat regimen. Strikingly, the co-absence of Znt8 and Sst led to a pronounced disruption in insulin secretion compared to mice with isolated deficiencies. We also evaluated the influence of a prevalent variant (rs13266634) within the Znt8 gene on glucose metabolism and lipid parameters in 349 healthy participants. Our findings delineated that those with the CC genotype exhibit a reduced insulin response after a mixed macronutrient tolerance test. In contrast, carriers of the Tallele appear to experience delayed postprandial blood triglyceride clearance, particularly in male and overweight subjects. In summary, this research underscores the pivotal roles and significant interplay of Znt8 and Sst play in metabolic health. These findings would provide new research targets to uncover the role of ZNT8 and SST in the development of metabolic diseases, such as T2D and obesity.

BackgroundGenetic polymorphisms are known to affect fasting blood lipid levels, but their effects in the context of a high-fat meal challenge are less well characterized. This study investigates the association between SNPs in lipid transport genes and post-prandial blood lipid profiles in healthy adults in the U.S.

MethodsSubjects (n = 349) were 18-66 years of age and balanced by sex (48% male, 52% female). They had body-mass indices (BMI) ranging from 18.5 to 45.0 kg/m2 and completed the cross-sectional Nutritional Phenotyping Study. We assessed informative single nucleotide polymorphisms (SNPs) in five lipid transport genes (APOA5, APOB, APOC3, APOE, and LDLR). The association between serum lipid markers and genotypes was evaluated separately for each SNP using an analysis of variance (ANOVA) and pairwise interaction tests adjusted for sex, age, and BMI. Results Women carrying the C allele of rs3135506 in APOA5 and men carrying the C allele of rs429358 in APOE had reduced fasting and postprandial HDL-cholesterol levels. The C allele in APOE was also correlated with increased LDL-C. The TT genotype of rs2854116 in APOC3 was associated with elevated total cholesterol. Additive interactions were detected between APOA5 and APOE and between APOC3 and APOE risk alleles. Nevertheless, the tested SNPs had little impact on the postprandial triglyceride responses to the high-fat challenge meal. Additionally, APOB (rs1042034) or LDLR (rs2228671) SNPs had no significant effect on serum triglyceride, cholesterol, or free fatty acid levels.

ConclusionsFasting and postprandial cholesterol levels are strongly correlated with APOA5, APOE, and APOC3 SNP genotypes in healthy adults. Sex increases the genetic impact of all tested SNPs on lipid profiles.